Benzene: Electrophilic Aromatic Substitution

• The characteristic reaction of benzene is electrophilic aromatic substitution, where a hydrogen atom is replaced by an electrophile.
• Benzene is especially stable, so reactions that keep the aromatic ring intact are favored; addition breaks aromatic stability, which is unfavorable.

Electrophilic Aromatic Substitution

• Reactions of benzene differ from unsaturated hydrocarbons, because addition would yield are non-aromatic product.
• Substitution of a hydrogen keeps the aromatic ring intact.
• Electrophilic aromatic substitution has several common examples.

Examples of Electrophilic Aromatic Substitution

• All reactions have specific conditions and their own rules.
• Halogenation replaces H with X (Cl or Br), using X2 and FeX3. -The electrophile is Cl or Br.
• Nitration replaces H with NO2, using HNO3 and H2SO4 to form nitrobenzene.
  • The electrophile is NO2.
  • This reaction produces nitro group and its nitrogroup is useful for synthesis
• Sulfonation replaces H with SO3H, using SO3 and H2SO4.
  • Benzensulfonic acid is produced.
  • The electrophile is SO3H
• Friedel-Crafts alkylation replaces H by R, using RCl and AlCl3 as a catalyst, leading to an alkyl benzene (arene).
  • The electrophile is R.
• Friedel-Crafts acylation replaces H by RCO, using RCOCl and AlCl3 to form a ketone.
  • Acetyl group results, with two R groups.
  • The electrophile is R-C=O.

Mechanism of electrophilic aromatic substitution

• Regardless of the electrophile used, all reactions occur by the same two-step mechanism:
  • The electrophile E⁺ adds, forming a resonance-stabilized carbocation in rate-determining step.
  • A base removes the proton on the carbon bonded to the electrophile, reforming the aromatic ring.
• In the first step of electrophilic aromatic substitution, a carbocation forms, and three resonance structures can be drawn.
• Always draw the H atom on the carbon bonded to E to remember that it’s the only sp³ hybridized carbon in the carbocation intermediate.
• In a given resonance structure, the positive charge is always located ortho or para to the new С-E bond. -Therefore in the hybrid, the charge is delocalized over three atoms of the ring.
• The mechanism has two steps, so there are two energy barriers.
  • Step 1 is rate-determining, its transition state is at higher energy.

Halogenation

• In halogenation, benzene reacts with Cl2 or Br2 in the presence of a Lewis acid catalyst, such as FeCl3 or FeBr3, to give aryl halides chlorobenzene or bromobenzene, respectively.
• Reactions with I2 and F2 are not synthetically useful because I₂ is too unreactive and F₂ reacts too violently.
• In bromination, a Lewis acid-base reaction of Br2 with FeBr3 forms a species with a weakened Br-Br bond that serves as a source of Br+.
• The electrophile's addition forms in a new C-Br bond and resonance-stabilized carbocation.
• FeBr4 removes the proton on the carbon bonded to the electrophile, reforming the aromatic ring.
  • The Lewis acid catalyst FeBr3 is regenerated for another reaction cycle.
• Chlorination proceeds by a similar mechanism.

Biologically Active Alkyl Chlorides

• Alkyl chlorides appear in compounds such as Bupropion
• Alkyl chlorides appear in compounds such as Chlorpheniramine
• Alkyl chlorides appear in compounds such as 2,4-D and 2,4,5-T
• Herbicides were used extensively during the Vietnam War causing concentrated herbicide by-products in the soil.

Nitration and Sulfonation

• Nitration and sulfonation introduce two different functional groups into the aromatic ring.
• Nitration is especially useful because the nitro group can be reduced to an NH2 group.
• In the nitration mechanism, generation of the electrophile requires strong acid.

Sulfonation Mechanism

• In sulfonation, electrophile generation also requires strong acid.

Friedel-Crafts Alkylation

• In Friedel-Crafts alkylation, treatment of benzene with an alkyl halide and a Lewis acid (AlCl3) yields an alkyl benzene.

Electrophiles in Friedel-Crafts Alkylation

• For CH3Cl and 1° RCl, the electrophile is a Lewis acid-base complex.
• For 2° and 3° RCl, carbocation rearrangements on 2 and 1 occur under special conditions
• Friedel-Crafts alkylation with tertiary carbocation proceeds through the addition of the carbocation electrophile. AICI4 removes a proton to re-form the aromatic ring

Other facts applicable to Friedel-Crafts Alkylation

• Vinyl halides and aryl halides do not react.
• Rearrangements can occur.

Friedel-Crafts Alkylation Involving Carbocation Rearrangement

• In formation there is an alkyl chloride.
• There is also a two-step mechanism for electrophilic aromatic substitution.

Rearrangements of Primary Alkyl Halides

• Rearrangements can occur even when no free carbocation is formed initially.
• H shifts to make a LG leave preventing 1 carbo-cation forming

Other Carbocations for Alkylation

• Functional groups that form carbocations be used as starting materials in a Friedel-Crafts Alkylation
• Protonation of an alkene forms a carbocation serving as an electrophile for Friedel-Crafts Alkylation.
• Protonation of an alcohol, followed by loss of water, likewise forms a carbocation.
• Carbocations formed in the presence of benzene can then substitute onto the ring by the usual mechanism.

Freidel-Crafts Acylation

• In Friedel-Crafts acylation, benzene rings are treated with an acid chloride (RCOCl) with AlCl3 to form a ketone
• The new group bonded to the benzene ring is called an acyl group, and the transfer of an acyl group from one atom to another is acylation.
• Lewis acid AICI3 ionizes the carbon-halogen bond of the acid chloride = acylium ion
• The positively charged carbon atom of the acylium ion goes on to react with benzene in the two-step machanism of eletrophilic aromatic substitution

Intermolecular Freidel-Crafts Reactions

• Starting materials containing both a benzene ring and an electrophile and capable of Intramolecular Freidel-Crafts Reactions
• An example is the alpha-tetralone-new C-C bond
• Intramolecular Friedel-Crafts acylation a product containing a new six-membered ring converted to LSD in several steps

Substituent Effects with Substituted Benzenes

• Each substitiuent either increases or decreases the electron density in the benzene ring, this affectsing the course of electrophilic aromatic substitution
• Donation of electron density to the ring makes benzene more electron rich
• Withdrawl of electron density from the eelectrones makes benzene less electron rich
• Electrophilic substitution on and already substitued benzene produces isomers, some of which are favored over other

Inductive effects

• Atoms more electronegative than carbon (N, O, and X) pull electrons away from carbon and thus exhibit and electron -withdrawing inductive effect
• Polarizable alkyl groups donate electron density, and thus exibit and electron-donating inductive effect
• N is more electronegative than C, it inductively withdrawls electron density, resulting in less reactivity
• Alkyl groups are polarizable, making them electron-donating groups, resulting in greater reactivity

Resonance Effects

• Resonance effects only obsorved with subsituents containing lone pairs or pi bonds.
• And = donating resonance effects when resonance structures place nagative charge to carbonos of benzene ring
• Withdrawing : when resonance structres place upositive charge on carbons of benzene wing

Electron effects

• Things having lone pairs and density is benzene ring put density at o,p positions

Electron Withdrawing resonance

• Where has positive charge on carbons if the and O/p have less electron density, meta positions more reactive

Reactivity Summary

• Alkyl substituted benzeneis are more electron rich than benzene itself .

Electron donors in reactions

• Resonance predominates.

Effects for directing EWG and EDG

• Resonance the e dominant effect when there is Electron donating The inductive effect dominates and so the benzene for Electro with and results inn Inductive with decreases and the Electron Withdrawn effects and result to decrease.

Summary of groups

• Groups with nitrogen and or oxygen are electron donators.
• Groups with halogen.
• Groups Y, with a delta + or +.

Directing groups with electrons

NH2 donates electron to make benzene ring less rich, CHO group with drawls electron density marking it with electrons

Orientation effects

The rate of reaction is such in that what makes them faster or slower than benzene is such how there directs new groups

Orientating substituents

All substituents activating a benzene ring direct subsitution to ortho para.

• Substituents are activators.
• Weakest due to having no one pair alkyIs.
• Halogens are drawing subs. Halogens can Ew, but not meta

Directers for substituents

All meta director and directing the ring all meta directing the ring. Directing all meta.

Substituents that draw the electron with

The key to thiss

All orthor para directing are R groups or having not born electron pains on the the adam boded to benzyke ring

• All beta directly he’s have and pull for for all part you positive charge and arm it

Activate / deactivate the ring

• To understand how. So she when she actually the act What must look at this stuff for electric aromatic subsistutes first you see the form of the electropole and how it resonates then it is a stable carbacation the lower energy you more stable the carbonation

The most stable

• Specific stabilty You got to stabilize the carbon

Donating = . Lower Ea Endthos

Energy levels

Electrode or groups they'd stabilizer carbonation and increase the rate of friction. Electrode or groups they stabilise the carbonation and decrease level reduce rate to the reation

Orientating benzenes

There are two general types of aura para directors on all general types of the director which include

• all para directors have a electron paid

Effect of resonance

1. Resonance must be drawn to identify effects. Draw resonating structure to identify effects which are in their state reaction

Activating direct

• A alkyl group directors electric attic and or and it stabilize the carbon station Amino group with electrons director electric all tax and it has resonance Benzylic location

Stabilizing a nitro group

• NO is for you are you are 0

Summary

Halogens are always actie and withdrwaing and directing

Rxns for activate rings

Strongly activate rings are the derivatives (OH,NH2) derivatives (OR,NHR,NR2) And treated with x2 the

• X3 will undergo the poly halogenation
• Mmono subsistsion of hydrogen bio bi or occur with BL2 alnoe and wihtout a aed catalyist to from a micture the orhtylo or param prarcucts

Reactions deactivate groups rings

• NOO2 Any is not strong enough then this will not undergo Fredel craft reaction

Friedel-Crafts

Complex between Nh2 group deactivated . Polysubstitution does not occur because of this Treatment is necessary Allos a form then a carbon stabilized subste

Directing

• Directing can occur by and it the effect force each of of one and or to the other The more is force the best is

Synthesis

• Substituted bezedene direct it better subsitute 1 Put Me first and it nitro after with c1/c1 as its meta It to not axidiase myth and but after the card box lix at or meta